1. Field of Invention
This invention relates to substituted benzoate ester prodrug derivatives of estrogens, pharmaceutical compositions containing prodrugs of estrogens, methods of contraception and treatments of disorders related to estrogen insufficiency using the prodrugs, and methods for preparing the prodrugs.
Prior Art
.beta.-estradiol is the primary biosynthetic product found in mammalian estrogenic hormones, and is the most potent naturally occurring estrogen. Extensive literature exists on the biochemistry and physiology of this substance, and on its use in hormone replacement therapy and contraception. Although extremely potent when administered parenterally, this compound elicits greatly reduced estrogenic effects when administered orally.
Ethynyl estradiol is a semi-synthetic estrogen, first reported by Inhoffen et al., Chem. Ber., 71, 1024 (1938). This compound provides greater estrogenic activity than .beta.-estradiol when administered orally, and is widely used in hormone replacement therapy and contraception. This compound and its preparation is disclosed in U.S. Pat. No. 2,243,887, issued June 3, 1941, to A. Serini et al.; U.S. Pat. No. 2,251,939, issued Aug. 12, 1941, to J. Kathol; U.S. Pat. No. 2,265,976, issued Dec. 9, 1941, to H. H. Inhoffen et al.; and U.S. Pat. No. 2,267,257, issued Dec. 23, 1941, to L. Ruzicka.
.beta.-estradiol 3-benzoate is disclosed by U.S. Pat. No. 2,054,271 (to Schwenk and Hildebrandt, 1936), and is widely used as a long-acting parenteral estrogenic drug for intramuscular injection.
Of the simple esters of .beta.-estrodiol such as the benzoate, the acetate and the propionate, which all result in prolonged activity when administered intramuscularly; the benzoate is most preferred because it is absorbed more slowly. These compounds show a marked decrease in activity when administered orally due to destruction by the intestinal bacteria and the liver.
Many disclosures of synthetic substances structurally related to estradiol which have been esterified with benzoic acid or hetero-aryl carboxylic acids can be found in the literature, with estrogenic and non-estrogenic pharmacological activities reported. A few examples are U.S. Pat. No. 3,347,880 (to Robinson, 1967), U.S. Pat. No. 3,634,404 (to Marshall, 1972), U.S. Pat. No. 4,110,324 (to Gueritee, 1978), Eur. Patent Appl. 4898 (to Prezewowsky et al., 1979), and German Pat. No. 3,144,049 (to Bermejo-Gonzales et al., 1983).
.beta.-Estradiol 3-p-bromobenzoate was reported by Y. Tsukuda et al., J. Chem. Soc., (B), 1387 (1968), and was used in an X-ray crystal structure determination.
Substituted benzoate esters of .beta.-estradiol with the formula ##STR1## wherein X=4-CH.sub.3, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-NO.sub.2, 4-OCH.sub.3, or 4-OC.sub.5 H.sub.9 are disclosed in German Patent No. 1,961,984 (1970, to Ercoli et al) and in Gardi et al., J. Med. Chem., 16, 123 (1973) as intermediates to orally active 17-enolethers of these compounds.
4-Alkoxybenzoate esters of .beta.-estradiol are reported by Doerfler et al., Stud. Biophys., 80, 59 (1980). The phase transition energetics of these compounds as liquid crystals are described in this publication.
Substituted aminomethylbenzoate esters of .beta.-estradiol with the formula ##STR2## wherein R=CH.sub.2 CH.sub.2 Cl or --CH(CH.sub.3)CH.sub.2 Cl are disclosed by M. Elian et al., Eur. J. Med. Chem. Chim. Ther., 18, 385 (1983), and by Romanian Patent No. 81,034 (1983, to Duvaz et al.). These compounds are described as alkylating agents with antineoplastic activities.
The radio-labelled 2-iodobenzoate of estradiol is reported by Brandau et al., Nuklearmedizin, Suppl., 20, 726 (1984), and was prepared by iodine-131 exchange with the corresponding 2-bromobenzoate ester.
The oral administration of many drugs will elicit a substantially lesser response as compared to an equal dose administered parenterally. This reduction in potency commonly results from the extensive metabolism of the drug during its transit from the gastrointestinal tract to the general circulation. For example, the liver and intestinal mucosa, through which an orally administered drug passes before it enters the systemic circulation, are very active enzymatically and can thus metabolize the drug in many ways.
When an orally administered drug is rapidly metabolized to an inactive or significantly less active form by the gastrointestinal system or liver prior to entering the general circulation, its bioavailability is low. In certain circumstances, this problem can be circumvented by administering the drug by another route. Examples of such alternative routes include nasal (propranolol), sublingual (nitroglycerin) and inhalation (cromolyn sodium). Drugs administered by these routes avoid hepatic and gut-wall metabolism on their way to the systemic circulation.
In some instances, the presystemic metabolism of certain orally administered drugs can be overcome by derivatization of the functional group in the molecule that is susceptible to gastrointestinal or hepatic metabolism. This modification protects the group from metabolic attack during the absorption process or first pass through the liver. However, the masking group must ultimately be removed to enable the drug to exert its maximum effect. This conversion may take place in blood or tissue. (Since the chemical group used to alter the parent drug will eventually be released into the body, it must be relatively non-toxic.) These types of masked drugs are usually referred to as prodrugs.
There are a number of examples in the literature which demonstrate the feasibility of the prodrug concept. However, it is apparent from these published studies that each drug class must be considered by itself. There is no way to accurately predict which prodrug structure will be suitable for a particular drug. A derivative which may work well for one drug may not do so for another. Differences in the absorption, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design.
.beta.-estradiol, although a potent estrogenic compound, undergoes extensive gastrointestinal and/or hepatic first-pass metabolism upon oral delivery, and thus has very significantly reduced bioavailability. Ethynyl estradiol is a potent semi-synthetic estrogen which shows enhanced oral bioavailability over .beta.-estradiol, but still suffers from gastrointestinal and/or hepatic first pass metabolism after oral dosing.
None of the references cited, nor any known reference, suggest the novel substituted benzoate esters of estrogens of the present invention, or their desirability as prodrugs of estrogens. Particularly unexpected is the fact that the substituted benzoate esters of this invention exhibit significantly improved bioavailability and extended duration of action when administered orally.